| 名稱 | BMS-345541 |
| 描述 | BMS-345541 (IKK Inhibitor III) is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM, respectively. |
| 細(xì)胞實(shí)驗(yàn) | 1×105 cells per well are plated in six-well plates with 10% fetal bovine serum medium overnight to allow cell adhesion. Cells ae cultured in medium containing BMS-345541 for 72 hours of treatment. Cells are counted with a hemocytometer.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Enzyme Assays: Assays measuring the enzyme-catalyzed phosphorylation of GST-IκBα are performed by adding enzyme (a final concentration of 0.5 μg/mL) at 30 ℃ to solutions of 100 μg/mL GST- IκBα and 5 μM [33P]ATP in 40 mM Tris HCl, pH 7.5, containing 4 mM MgCl2, 34 mM sodium phosphate, 3 mM NaCl, 0.6 mM potassium phosphate, 1 mM KCl, 1 mM dithiothreitol, 3% (w/v) glycerol, and 250 μg/mL bovine serum albumin. The specific activity of [33P]ATP used in the assay is 100 Ci/mmol. After 5 min, the kinase reactions are stopped by the addition of 2× Laemmli sample buffer and heat-treated at 90 ℃ for 1 min. The samples are then loaded on to NuPAGE 10% BisTris gels. After completion of SDS-PAGE, gels are dried on a slab gel dryer. The bands are then detected using a 445Si PhosphorImager, and the radioactivity is quantified using ImageQuant software. Under these conditions, the degree of phosphorylation of GST-IκBα is linear with time and concentration of enzyme. |
| 體外活性 | 75 mg/kg BMS-345541處理過的腫瘤小鼠表現(xiàn)對SK-MEL-5,A375和Hs 294T生長的有效抑制和對照組相比抑制率分別為86％,69％和67％.BMS-345541（100 mg/kg）將累積性關(guān)節(jié)炎損傷評分從4.4降低至0,伴隨著較低的脛骨關(guān)節(jié)退化和炎癥嚴(yán)重程度,滑膜增生,骨吸收和軟骨侵蝕.BMS-345541劑量依賴性地抑制了IL-1β信號,100 mg/kg劑量組動物顯示與無疾病對照動物相當(dāng)?shù)乃?口服100 mg/kg BMS-345541時,降低了葡聚糖硫酸鈉誘導(dǎo)的結(jié)腸炎的小鼠的重量比,臨床腸道評分,平均損傷評分和平均炎癥評分,分別是0.86（vs對照組的0.77）,1.0（vs對照組的2.5）,5.66（vs對照組的8.52）,6.82（vs對照組的12.33）. |
| 體內(nèi)活性 | 5 μM BMS-345541在BE-13和DND-41細(xì)胞中,誘導(dǎo)細(xì)胞停滯在細(xì)胞周期中的G2/M期,并阻礙RPMI-8402細(xì)胞停留在亞-G1期。5 μM BMS-345541處理16小時導(dǎo)致凋亡細(xì)胞的增多,伴隨著procaspase-8,procaspase-3和聚（ADP-核糖）時間依賴性的解離。5 μM BMS-34554誘導(dǎo)IκBα和p65的時間依賴性的去磷酸化。10 μM BMS-345541抑制正常人類表皮黑素細(xì)胞和轉(zhuǎn)移性黑色素瘤細(xì)胞（SK-MEL-5,A375和HS294T）的生長,72小時抑制率分別是由96％和99％。10 μM BMS-345541導(dǎo)致IKK活性降低76％,NF-kB活性降低95％,以及CXCL1產(chǎn)生。 BMS-345541劑量依賴性地抑制THP-1單核細(xì)胞中TNF-α刺激的IκBα的磷酸化,IC50為4 μM。BMS-345541在人臍靜脈內(nèi)皮細(xì)胞中,抑制TNFα-誘導(dǎo)的ICAM-1和VCAM-1的表達(dá),IC50為5 μM。BMS-345541結(jié)合到IKK-1和IKK-2的變構(gòu)位點(diǎn),進(jìn)而影響亞基的不同的活性位點(diǎn)。BMS-345541影響幾種有絲分裂細(xì)胞周期轉(zhuǎn)換,包括進(jìn)入有絲分裂,早中期至后期的進(jìn)展和胞質(zhì)分裂。在細(xì)胞中加入BMS-345541導(dǎo)致細(xì)胞停留在G期,并抑制Aurora A,B和C的激活,Cdk1的激活和組蛋白H3的磷酸化。BMS-34554處理導(dǎo)致T-ALL細(xì)胞中FOXO3a的核易位,包括控制p21 CIP1基因的表達(dá)水平。BMS-345541還抑制兒童患者的T-ALL原代細(xì)胞的生長,IC50為2-6 μM。 |
| 存儲條件 | store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 9 mg/mL (35.24 mM)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | BMS 345541 | Inhibitor | inhibit | IκB kinase | IKK | BMS-345541 | I kappa B kinase |
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